RNA-protein interactions play critical roles in cellular regulatory processes and in the life cycles of many pathogenic viruses, including HIV, hepatitis C, and West Nile virus, and thus represent attractive targets for therapeutics. Much of our previous work has centered on identifying and characterizing the components of key interactions and developing cell-based reporters to accurately monitor RNA-protein interactions. Here we focus on developing targeted assays for inhibitor screening. The cell-based screens described incorporate a system of genetic reporters designed to recapitulate RNA-protein interactions in a native mammalian environment and to enable screens with high sensitivity and specificity. As proof-of-principle, reporters cell lines will be developed and used to identify inhibitors of the HIV Rev-Rev Response Element (RRE) interaction from combinatorial zinc finger libraries. The development of high-throughput genetic methods to identify specific inhibitors of RNA-protein interactions is expected to help in the discovery of drugs directed against novel therapeutic targets.